Cancer is one of the most prominent causes of human death. For example, breast cancer is one of the most common causes of cancer in women. The likelihood of developing invasive breast cancer during a woman's lifetime is approximately 1 in 7. In this aspect it is expected that the global market for breast cancer therapy and diagnosis is about 12 to 15 Billion US Dollar by 2015. There is an intense search for new compounds useful for the treatment and diagnosis of cancer, e.g. solid tumors, in particular breast cancer.
Anti-cancer drug discovery is now driven by the numerous cancer-specific molecular alterations identified in tumor cells over the past decade. To exploit these alterations, it is necessary to understand how they define a molecular context that allows increased sensitivity to particular compounds. Traditional genetic approaches together with the new wealth of genomic information in both human and model organisms open up strategies by which drugs can be profiled for their ability to selectively kill cells in a molecular context matching those found in tumors. Similarly, it may be possible to identify and validate new targets for drugs that would selectively kill tumor cells with a particular molecular context.
The recent remarkable progress in identifying cancer-specific molecular alterations in human tumors has unfortunately not been paralleled in the field of anti-cancer drug discovery. The shortage of effective anti-cancer drugs is due in part to the fundamental difficulties associated with the development of any safe and effective drug. For example, it remains a formidable task to design small molecules that alter the function of macromolecules with both sensitivity and specificity (for example, an enzyme with a small active site). It is even more difficult to inhibit protein-protein interactions mediated over a large surface, or to restore function to a defective protein (such as an inactive tumor suppressor gene). Even when successful, massive efforts are required—often measured in years to decades—from dozens of chemists, biochemists and toxicologists.
Considerable commercial and academic resources are directed to identification of candidate therapeutic agents for the treatment of various types of cancer. For example in case of breast cancer, herceptin was developed representing a humanised antibody approved for the treatment of HER2-positive metastatic breast cancer. Other newly designed therapeutic agents include humanised anti-CD20-antibodies, like Rituximab. A further example, Tykerb is a dual kinase inhibitor which inhibits both ErbB-2 and EGFR kinases and may be more effective than e.g. the compound herceptin.
Unfortunately, the vast majority of genes that show cancer-specific alterations in tumors do not present pharmaceutically tractable targets for the creation of small molecule therapeutics.
The most common molecular targets, which have proven useful in the identification of small molecule drugs, are enzymes, receptor-ligand pairs, and occasionally specific protein-protein interactions. Selective inhibitors of these types of molecular processes can readily be found that block the biochemical reactions carried out by these molecules (Gibbs, J. B. and Oliff, A., in Cell (1994) 79: 193-8). However, many of the genetic abnormalities found in human cancers represent loss of function mutations that eliminate or severely reduce the biochemical activities governed by these proteins. Since these molecules have already lost their normal biochemical activities, blockade of their physiological functions by drug inhibitors offers no therapeutic benefit. Thus, the list of potential cancer drug targets is much smaller than the long list of genes that are altered in human tumors.
Typically, the various types of cancers, for example breast cancer, are multifactorial diseases with no standardized medication available for patients. In spite of major advance in early detection and subsequent therapy, diagnosis and treatment as well as stratification of treatment regimen remains a major clinical and social problem.
Thus, the object of the present disclosure is to provide novel therapeutic agents for the use in prophylaxis or treatment of cancers, in particular for the treatment of breast cancer.